TGF-β Inhibitor Potentiates Osimertinib-Induced Anti-Tumor Immunity in Egfr-Mutant Lung Cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Immunotherapy for EGFR-mutated NSCLC faces challenges due to immunosuppressive cytokines like TGF-β induced by EGFR-TKIs.
• EGFR-TKIs can paradoxically increase TGF-β, potentially limiting their effectiveness in non-small cell lung cancer.
• Targeting TGF-β alongside EGFR inhibition may overcome treatment resistance in EGFR-mutated NSCLC.

Purpose of the Study:

• To investigate if TGF-β inhibition can enhance osimertinib-induced antitumor immunity in a mouse model of EGFR-mutated lung cancer.
• To evaluate the efficacy of combining osimertinib with TGF-β inhibitors (nintedanib or vactosertib) in vivo and in vitro.
• To analyze the impact of combination therapy on the tumor microenvironment and immune cell populations.

Main Methods:

• Utilized a syngeneic mouse model of EGFR-mutated lung cancer (subcutaneous tumor xenografts).
• Assessed antitumor effects of osimertinib combined with nintedanib (indirect TGF-β inhibitor) or vactosertib (direct TGF-β inhibitor).
• Analyzed tumor microenvironment changes via immunohistochemistry, western blot, and flow cytometry.

Main Results:

• Combination therapy with osimertinib and nintedanib significantly enhanced antitumor effects compared to osimertinib monotherapy in vivo; no additive effect observed in vitro.
• Osimertinib upregulated TGF-β expression; combination therapy decreased TGF-β and SMAD2/3 expression.
• Combination therapy increased effector T cells and Granzyme B+ areas while decreasing CD206+ cells, indicating enhanced anti-tumor immunity.

Conclusions:

• Combination of osimertinib with TGF-β inhibitors (nintedanib or vactosertib) potentiates osimertinib-induced antitumor immunity in EGFR-mutated NSCLC.
• This combination strategy modulates the tumor microenvironment, promoting an anti-tumor immune response.
• Findings support further clinical investigation of osimertinib and TGF-β inhibitor combinations for EGFR-mutated NSCLC treatment.